The objective of the proposed studies is to investigate the role of NMDA receptors in the reinforcing effects of cocaine and the reinstatement of cocaine seeking behavior using a behavioral, pharmacological, and genetic approach. A mouse self-administration model is employed to assess cocaine self-administration behavior in mice with a deletion in the essential NR1 subunit of the NMDA receptor (NR1-KD). In Specific Aim I, cocaine self-administration behavior is assessed in NR1 mutant mice and wild-type littermate controls, Complete dose-effect functions for cocaine self-administration are generated on both fixed and progressive ratio schedules of reinforcement to compare the potency and reinforcing efficacy of cocaine in NR1 mutant and wild-type mice. Specific Aim II extends the findings of Specific Aim I and examines the role of NMDA receptors in cocaine relapse by assessing reinstatement of drug self-administration behavior in two models of human drug relapse: 1) following exposure to priming doses of cocaine or 2) following presentation of cues previously associated with cocaine administration in NR1 mutant mice and wild-type littermate controls. Collectively, the proposed studies will further our understanding of the role of glutamatergic mechanisms in the reinforcing effects of cocaine and reinstatement of cocaine-seeking behavior and may lead to new pharmacotherapeutic strategies for the treatment of drug dependence.